Glutamate-opioid interactions in alcohol drinking behaviors

Overview

Principal Investigator: Dr. Suchitra Krishnan-Sarin. This project extends hypotheses from Projects 1-3 and builds on exciting preliminary findings from prior CTNA projects using our alcohol self-administration paradigm. In CTNA-1, we observed that naltrexone reduced drinking in drinkers with a family history of alcoholism (FHP), but not in family-history negative (FHN) drinkers, with no significant reductions in the stimulatory effects of alcohol or alcohol craving in either group. In CTNA-2, memantine reduced the stimulatory effects of alcohol and alcohol craving, with trends towards reduction in drinking in FHP, but not FHN drinkers, in this ongoing study. In the current CTNA project, we will conduct a "proof of concept" evaluation in FHP drinkers of whether naltrexone and memantine have synergistic effects on reducing alcohol effects, alcohol craving, and alcohol drinking.

Activities

We will test the hypothesis that by blocking both opioid and NMDA receptors, one may synergistically target multiple neurochemical and behavioral processes, leading to optimal reduction of alcohol drinking. This “proof of concept” trial will be conducted in FHP drinkers in whom we have observed reduction in alcohol reward with MEM and in alcohol drinking with NTX. We will conduct innovative explorations of the predictive utility of impulsive responding, implicit alcohol motivational tendencies, and variations in genes for opiate receptors and for signal transduction proteins linking dopamine and glutamate receptors upon alcohol drinking behaviors.

86 non-treatment-seeking, alcohol-dependent, FHP heavy drinkers will participate in a three-week crossover study consisting of two weeks of outpatient treatment with NTX and MEM/PLA (placebo) separated by a 6-day washout phase. This design will allow optimal use of CTNA resources to examine whether reducing the reinforcing effects of alcohol using MEM will augment the impact of NTX, which seems to be acting on alcohol drinking without reducing alcohol reinforcement. We will use the 40 mg dose of MEM (which reduced alcohol reward and possibly drinking) and the 50 mg dose of NTX, which reduces alcohol drinking. Tolerability of combining NTX and MEM will be monitored. Drinking behavior and other outcomes will be measured using the ADP, at baseline, and then again at the end of each treatment week.

Participation Opportunities

Dr. Dana Cavallo
34 Park St., CMHC
New Haven, CT 06519
Phone: 203-974-7607

Nicholas Franco
34 Park St., CMHC
New Haven, CT 06519
Phone: 203-974-7679
e-mail: nicholas.franco@yale.edu

Relevant Publications

  1. Adinoff, B., Junghanns, K., Kiefer, F., Krishnan-Sarin, S. (2005). Suppression of the HPA Axis Stress-Response:  Implications for Relapse. Alcoholism: Clinical and Experimental Research.  29(7): 1351-5.
  2. McKee, S. A., Krishnan-Sarin, S., Shi, J., Mase, T., & O’Malley, S. S. Modeling the effect of alcohol on smoking lapse behavior. (2006). Psychopharmacology. 189(2):201-10.
  3. Duhig, A.M., Maciejewski, P.K., Desai, R.A., Krishnan-Sarin, S., Potenza, M.N. (2007). Characteristics of adolescent past year gamblers and non-gamblers in relation to alcohol drinking.  Addictive Behaviors.  32(1):80-9.
  4. Krishnan-Sarin, S., Krystal, J.H., Shi, J., Pittman, B., O’Malley, S.S. (2007). Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking.  Biological Psychiatry. 62: 694-7.
  5. McKee, S.A., O’Malley, S.S., Shi, J., Mase, T., Krishnan-Sarin, S. (2008).  Effect of transdermal nicotine replacement on alcohol responses and alcohol self-administration.  Psychopharmacology. 196:189-200
  6. Leeman, R. F., McKee, S. A., Toll, B. A., Krishnan-Sarin, S., Cooney, J. L., Makuch, R.W., & O’Malley, S. S. (2008).  Risk factors for treatment failure in smokers: Relationship to alcohol use and to lifetime history of an alcohol use disorder. Nicotine & Tobacco Research. 10(12): 1793-1809.
  7. Schepis, T.S., Desai, R.A., Smith, A.E., Cavallo, D.A., Liss, T.B., McFetridge, A., Potenza, M.N., Krishnan-Sarin, S. (2008). Impulsive sensation seeking, parental history of alcohol problems and current alcohol and tobacco use in adolescents.  Journal of Addiction Medicine.  2 (4): 185-193.
  8. Krishnan-Sarin, S., O’Malley, S.S., Krystal, J.H. (2009). Treatment Implications: Using Neuroscience to Guide the Development of New Pharmacotherapies for Alcoholism.  Alcohol Research and Health 31 (4): 400-407.